ATL is caused by the HTLV-1 retrovirus but it is unknown how this virus leads to cellular transformation. The only HTLV-1 gene product that is expressed in all ATL cells is HBZ but exactly how HBZ transforms T lymphocytes is unclear. Using genomic scale RNA interference, we identified a regulatory network involving the transcription factors BATF3 and IRF4 that is essential for ATL proliferation and survival. Through the use of available gene expression profiling data, we showed that BATF3/IRF4 downstream targets a hallmark of ATL that distinguishes it from other T-cell lymphoma subsets. We showed that BATF3/IRF4 are essential for ATL proliferation on our master regulators of gene expression in ATL cell lines in patient samples. Furthermore, we showed that HBZ upregulates expression of BATF3 and its target genes by binding to an ATL specific BATF3 super-enhancer. BET protein inhibitors collapse the transcriptional network directed by HBZ and BATF3/IRF-4. BET protein inhibitors are toxic for ATL cell line in patient samples ex vivo and block ATL xenograft growth. Our preclinical studies provide a solid rationale for the initiation of clinical trials of BET inhibitors in ATL. To investigate previously undescribed therapeutic targets in ATL, we performed a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screening to identify genetic vulnerabilities in ATL cells. CDK6 (cyclin dependent kinase 6) was the best scoring gene. This prompted us to focus on CDK6 as a therapeutic molecular target in ATL. Two sgRNAs targeting the coding sequence of CDK6 exhibited strong cytotoxicity for all of 5 ATL cell lines in a timed-dependent manner. The sgCDK6 mediated toxicity was mediated by G1 cell arrest and in part by apoptosis, and successfully rescued by retroviral induction of sgRNA resistant CDK6 cDNA in two ATL cell lines tested. Given that CDK6 was discovered as the best valuable target in ATL cells among 19, 144 genes, we extended our analysis to evaluate pharmacological inhibition of CDK6 in ATL cells. Palbociclib, FDA approved CDK4/6 inhibitor was toxic in 11 ATL cell lines and in 4 primary ATL cells but the range of IC50 values was relatively broad among ATL cell lines. We assessed TP53 status of ATL cell lines by Sanger sequencing and immunoblotting and identified that TP53 altered ATL cells (N=6) and exhibited significantly higher IC50 for palbociclib compared to TP53 intact ATL cell lines (N=5p 0.05). We treated a mouse xenograft model of TP53 intact ATL cell lines with palbociclib and observed significant inhibition of tumor growth without systemic toxicity. Our study demonstrates new therapeutic targets for ATL, and we propose that CDK6 inhibition with CDK4/6 inhibitor palbociclib together with biomarker analysis including TP53 status is worth being evaluated as a therapeutic strategy for ATL in future clinical studies by the group. In new studies we demonstrated bifurcation of signals for NK-cell survival and proliferation by trans-endocytosed versus soluble IL-15R apha-IL-15 complexes. We showed here that the entire membrane associated IL-15R alpha-IL-15 complex was transferred from presenting cells to NK cells through endocytosis and that this stimulated efficient phosphorylation of ribosomal protein S6 and proliferation. Conversely NK cell interaction with IL-15R alpha to IL-15 that was either surface bound or shed in soluble form resulted in preferential STAT5 phosphorylation and NK survival. These studies provided a mechanism for NK cell expansion that is not available to soluble IL-2 and has profound implication for the stimulation and use of NK cells in cancer immunotherapy.